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Comorbidities in rheumatic disease

Introduction

Patients with rheumatic disease often have one or more comorbid conditions. Improving our understanding of these comorbid conditions, particularly shared etiology of these conditions with rheumatic disease, may enhance our understanding of the pathophysiology of rheumatic diseases. Such increased understanding would improve our ability to effectively treat both the rheumatic disease and the comorbid conditions. Increased physician awareness of these frequent comorbid conditions is important to ensure optimal treatment of the patient to improve overall quality of life as well as rheumatic disease-specific outcomes.

This themed collection comprises a selection of recent full-text articles and chapters from the Springer Nature portfolio that discuss this important subject. 


General

Multimorbidity and rheumatic conditions—enhancing the concept of comorbidity

This paper reviews the conceptual differences between comorbidity and multimorbidity in rheumatology, and discusses the importance of a multimorbidity approach to treatment and research.

Summary
  • Patients with rheumatoid arthritis typically have comorbid conditions, with the number of such conditions increasing with age, disease duration and disease activity.
  • Comorbidity focuses on the index disease and addresses the co-occurrence of any distinct additional abnormalities – categorized based on causality (a disease followed by a pathophysiologically linked condition), complication (a complication of the index disease) and coincidence (occurs independently).
  • Multimorbidity can be defined as “coexistence of two or more chronic diseases in the same individual”, with no index disease defined and all morbidities considered to be of equal importance.
  • While there is a substantial body of research into the impact of comorbidities in rheumatoid arthritis, the implications of multimorbidity are less clear; however, evidence suggests that it is a major determinant of many health outcomes, including hospitalization and mortality.
  • A multidisciplinary approach is necessary when treating patients with multimorbidity, to ensure best possible patient-centered care, with minimization of costs and complications.
  • Multimorbidity involves putting the patient, rather than the index disease, at the centre of care, a move likely to have significant impact on diagnostic and treatment decisions.

Radner H et al. Nat Rev Rheumatol 2015;10:252–256. doi:10.1038/nrrheum.2013.212

Cardiovascular disease

Is the risk of cardiovascular disease altered with anti-inflammatory therapies? Insights from rheumatoid arthritis

This paper reviews the inflammatory process associated with metabolic diseases, and discusses ways anti-inflammatory agents influence these inflammatory processes and potentially impact cardiovascular disease risk.

Summary
  • Atherosclerosis, the major form of cardiovascular disease, is characterized by chronic low-grade inflammation, which is also a feature of several other diseases associated with increased cardiovascular disease risk.
  • In rheumatoid arthritis, unlike many of the metabolic diseases, the relationship between cholesterol and increased cardiovascular disease risk is not clear. In some cases, increased C-reactive protein (indicating increased cardiovascular disease risk) is associated with reduced circulating cholesterol – a phenomenon termed the lipid paradox.
  • Studies of various therapeutic agents targeting inflammation for the treatment of rheumatoid arthritis have shown increases in cholesterol levels, often with decreases, or no change, in cardiovascular disease risk – this may be because patients with rheumatoid arthritis have low cholesterol levels, so increases with therapy result in normalization of these levels.
  • There is increasing evidence to suggest that the hematopoietic system may be the link between increased cardiovascular disease risk and metabolic diseases.
  • It is proposed that alterations in hematopoiesis may be responsible for enhanced cholesterol catabolism: a direct correlation between hyperlipidemia and leukocyte number is routinely reported in humans, and currently available data demonstrate a link between arthritis-induced hematopoiesis and perturbations in circulating cholesterol levels.
  • Metabolic disorders such as diabetes and obesity may promote atherosclerosis by modulation of hematopoiesis and monocytosis.
  • The role of suppression of hematopoiesis and stem cell proliferation in the relationship between anti-inflammatory agents and increased cholesterol levels remains to be elucidated. Until a greater understanding is reached, close screening of all patients receiving anti-inflammatory agents should be mandatory for monitoring of cardiovascular risk in the case of dyslipidemia.

Kraakman​​​​​​​ MJ et al. Clin Trans Immunol 2016;5,e84. doi:10.1038/cti.2016.31

Cardiovascular comorbidity in rheumatic diseases

This paper discusses potential mechanisms linking rheumatoid arthritis and increased cardiovascular disease risk, with a focus on inflammation, and highlights the need for cardiovascular risk assessment and management in patients with rheumatoid arthritis.

Summary
  • Rheumatoid arthritis remains an independent risk factor for cardiovascular disease after adjusting for traditional risk factors.
  • The lipid paradox in rheumatoid arthritis, where a reduction in lipid levels is associated with higher cardiovascular risk, may be explained by modification of lipids by inflammation.
  • Other risk factors for cardiovascular disease in patients with rheumatoid arthritis include bodyweight and inactivity, diabetes and insulin resistance, cigarette smoking, hypertension, hyperhomocysteinemia and thyroid disease.
  • Genetic factors may play a role in the link between atherosclerosis and inflammatory joint disorders, particularly rheumatoid arthritis.
  • Inflammation is an important independent risk factor for cardiovascular disease, although the mechanisms by which inflammation increases this risk remain to be fully elucidated; inflammation may have effects on vascular function and morphology, plaque composition and prothrombotic phenomena.
  • Cardiovascular risk assessment should be part of routine care in patients with rheumatoid arthritis. However, cardiovascular risk is still underestimated in patients with rheumatoid arthritis and thus management of such risk remains less than satisfactory.
  • Cardiovascular risk management comprises three main principles: pharmacological management, nonpharmacological management (lifestyle interventions) and tight control of disease activity.

Nurmohamed​​​​​​​ MT et al. Nat Rev Rheumatol 2015; 11: 693–704. doi:10.1038/nrrheum.2015.112

Atherosclerosis in rheumatoid arthritis: is it all about inflammation?

This paper reviews the potential mechanisms by which atherosclerosis is accelerated in patients with rheumatoid arthritis, with a focus on inflammation.

Summary
  • Atherosclerosis is now recognized as a chronic inflammatory condition, in which both the innate and adaptive immune systems play key roles in initiation, progression and stability of lesions.
  • Both endothelial dysfunction and atherosclerosis are more prevalent among patients with rheumatoid arthritis than in the general population. Moreover, in those with rheumatoid arthritis, the rate of atherosclerosis progression is increased, plaque burden is greater and some evidence suggests that plaques may be more rupture prone.
  • Rheumatoid arthritis and cardiovascular disease share several risk factors. These include genetic risk factors (HLA-DRB1 polymorphisms, polymorphisms coding for nuclear factor κB [NFκB] signalling, MHC2TA polymorphism coding for MHC expression and IFR5 promoter polymorphism coding for interferon production), traditional risk factors (smoking, diabetes mellitus and obesity) and potential novel risk factors (periodontitis and rheumatoid arthritis-related autoantibodies).
  • While the prevalence of some of the traditional cardiovascular risk factors is increased in patients with rheumatoid arthritis, the relative contribution of these factors to cardiovascular risk appears to be lower than in the general population, with some evidence suggesting this may be due to the presence of inflammation in rheumatoid arthritis.
  • Traditional risk models underestimate the risk of cardiovascular events in patients with rheumatoid arthritis. Currently, no rheumatoid arthritis-specific risk prediction models incorporate traditional risk factors and disease-related factors, such as disease severity.
  • Treating the cardiovascular risk in patients with rheumatoid arthritis first involves estimation of this risk, management of traditional risk factors and consideration of the effects of treating inflammation – the results of studies examining the effects of specific drugs on cardiovascular risk are varied.
  • Further research is required to gain greater understanding of rheumatoid arthritis-specific mechanisms of atherosclerosis.

Skeoch S & Bruce IN. Nat Rev Rheumatol 2015;11:390–400. doi:10.1038/nrrheum.2015.40

Impact of disease activity and treatment of comorbidities on the risk of myocardial infarction in rheumatoid arthritis

This paper reports the results of a large observational cohort study of 11,285 patients, conducted to investigate the risk of myocardial infarction in patients with established rheumatoid arthritis.

Summary
  • This study had two aims:
    • to show the influence of risk factors, especially inflammation, on incidence of myocardial infarction (MI) in patients with rheumatoid arthritis
    • to investigate the impact of treatment of rheumatoid arthritis with disease-modifying antirheumatics (DMARDs) and concomitant glucocorticoids, and of cardiovascular comorbidities.
  • Data for this study came from the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT) – an ongoing observational cohort study enrolling patients at initiation of biologic DMARD or conventional synthetic DMARD after failure of at least one prior conventional synthetic DMARD.
  • A total of 11,285 patients were enrolled between 1 May 2001 and 31 October 2013, with 115 myocardial infarctions identified as a first cardiovascular event, and 112 eligible case-control pairs identified for analysis.
  • Among the 75 case-control pairs with at least one baseline cardiovascular comorbidity, those patients who developed an MI during follow-up were significantly less likely to receive medical treatment for their cardiovascular comorbidity than their corresponding controls.
  • The number of different DMARD episodes was significantly higher in patients with MI than in matched controls, with one episode in 51 cases (45.5 %), two episodes in 30 cases (26.8 %) and 3 or more episodes in 31 cases (27.7 %), compared with 77 (68.8 %), 19 (16.9 %) and 16 (14.3 %), respectively, in controls (p < 0.01).
  • At baseline, and during the first 6 months from baseline, inflammatory markers C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly elevated in MI cases compared with controls.
  • Adjusted multiple conditional logistic regression analysis did not show any association between risk of MI and treatment with tumour necrosis factor (TNF)-inhibitors or other biological DMARDs, and no significantly higher risk with glucocorticoids treatment; there was a strong association between logCRP and MI, but not raw CRP values, confirming the expected non-linear association.
  • The study findings confirm that management of cardiovascular comorbidities in patients with rheumatoid arthritis is unsatisfactory, and underlines the importance of a treat-to-target approach that considers global disease activity and CRP (as a measure of inflammation).

Meissner Y, Zink A, Kekow J, et al. Arthritis Res Ther 2016;18:183. doi:10.1186/s13075-016-1077-z

Managing cardiovascular disease risk in rheumatoid arthritis: Clinical updates and three strategic approaches

This review discusses current knowledge and gaps around cardiovascular risk management in rheumatoid arthritis.

Summary
  • Appropriate methods of assessing and managing the elevated cardiovascular risk in rheumatoid arthritis remain to be determined.
  • Three strategic approaches were considered for addressing this elevated cardiovascular risk:
    • Rheumatoid arthritis disease-centric approach
    • Assessment of comprehensive individual risk using risk scores
    • Management of traditional cardiovascular disease risk factors.
  • Using a rheumatoid arthritis disease-centric approach, recommendations include treat-to-target care (the new gold standard approach), stopping use of glucocorticoids or reducing to the lowest possible dose, and careful consideration of use of rheumatoid arthritis medications that impact cardiovascular disease risk.
  • Recommendations for an individual risk approach should involve comprehensive individual risk calculation using validated risk assessment tools or prediction scores, with EULAR guidelines recommending such assessment be performed at least every 5 years or at the time of significant changes in therapy.
  • For a traditional risk factor management approach, clinical population monitoring strategies should be employed regarding blood pressure, smoking status, diabetes, lipid levels (with statin therapy where appropriate), obesity and physical inactivity.
  • In the US, most rheumatoid arthritis visits occur in specialty clinics, thus it would be appropriate for such clinics to discuss prevention topics traditionally covered by primary care physicians to address cardiovascular risk management.

Chodara AM, Wattiaux A, Bartels CM. Curr Rheumatol Rep 2017;19:16. doi:10.1007/s11926-017-0643-y

Mental health

Affective disturbance in rheumatoid arthritis: psychological and disease-related pathways

This paper provides an overview of the relationship between mood disorders and rheumatoid arthritis, with a focus on potential mechanisms and possible therapeutic approaches.

Summary
  • Mood disorders, especially depression, occur with increased prevalence among patients with rheumatoid arthritis compared with the general population, with the notable exception of schizophrenia, which is less prevalent, probably due to the aberrant inflammatory cytokine profile apparent in schizophrenia.
  • Potential mechanisms underlying the association between rheumatoid arthritis and mood disorders include those related to physical symptoms, stress, fatigue, emotional status, cognitive responses (such as pain catastrophizing) and behavioural responses, as well as a postulated role of the reward circuitry and neural processing.
  • Social factors, including relationships with care providers, are an important consideration for mood disorders in rheumatoid arthritis and may also influence pain processing and disease activity.
  • Existing medical treatments for rheumatoid arthritis need to be complemented with psychological interventions – such as cognitive-behavioral therapy, meditation-based approaches and self-management programmes.
  • Work to reduce the social disconnect and stigmatization than can occur in rheumatoid arthritis, as well as interventions combining pharmacotherapy and psychotherapy, may be of importance for improving outcomes in rheumatological care.

Sturgeon JA, Finan PH, & Zautra AJ. Nat Rev Rheumatol 2016;12:532–542. doi:10.1038/nrrheum.2016.112

Are depression and anxiety associated with disease activity in rheumatoid arthritis? A prospective study

This one-year prospective study explored the relationship between depression, anxiety and rheumatoid arthritis disease outcomes.

Summary
  • While it is clear that the relationship between rheumatoid arthritis and mental health is bidirectional, there is a paucity of quality data detailing the nature of this relationship.
  • Consecutive patients were recruited from a hospital clinic waiting room; of 235 patients who completed the baseline questionnaire, 56 patients with verified rheumatoid arthritis were included in outcomes analyses.
  • Both depression and anxiety scores at baseline were associated with increased 28-joint disease activity score (DAS28) at 1-year follow-up, but this relationship was not significant after adjustment for baseline disease activity.
  • Depression and anxiety were significantly associated with the subjective components (but not the objective components) of the DAS28: tender joint count (TJC) and patient global assessment (PGA).
  • Neither depression nor anxiety at baseline were significantly associated with the odds of being in clinical remission at 1-year follow up.
  • These study findings suggest that depression and anxiety impact patient perception and behaviour rather than disease activity.
  • Depression and anxiety should be measured in routine clinical practice and as part of randomized controlled trials for new therapies in rheumatoid arthritis.

Matcham F, Ali S, Irving K, Hotopf M, Chalder T. BMC Musculoskelet Disord. 2016;17:155. doi:10.1186/s12891-016-1011-1

Psychological factors in arthritis: Cause or consequence?

This chapter provides a brief overview of the relationship between psychology and biology in arthritis, with a focus on the relative contribution of psychological factors to arthritis burden.

Summary
  • Recently, there has been a paradigm shift within medicine and public health, away from the traditional model where mind and body are separate, towards a ‘holistic’ model of health and illness. There is increasing evidence suggesting that psychological disorders and arthritis are intertwined.
  • The prevalence of depression in rheumatoid arthritis has been estimated to range from 13% to 20%, and current research suggests that between 21% and 70% of those with arthritis experience heightened levels of anxiety.
  • Depression and anxiety in those with arthritis have been shown to result from a complex interaction between physical and clinical predictors (functional impairment and disability, pain and disease activity, and fatigue) and psychosocial factors (sociodemographics, psychological vulnerability, coping efforts, social support and personality).
  • Available evidence suggests that depression and anxiety are largely associated with subjective rather than objective measures of disease – but the nature of the relationship between physical and psychological factors is complicated.
  • There are several proposed mechanisms for the depression-arthritis relationship. One such mechanism involves stress hormones, which are elevated in depression. This model, termed the allostatic load model, postulates that several maladaptive processes lead to lasting changes conducive to onset of diseases, including inflammatory diseases.
  • Overall, the relationship between psychological disorders, disease outcomes and psychological adjustment is extremely complex, with a cyclical relationship noted between pain, physical function and depression.

Harris ML.  In: Nicassio PM (Ed) Psychosocial Factors in Arthritis: Perspectives on Adjustment and Management. Springer International Publishing Switzerland. 2016:53-77. doi:10.1007/978-3-319-22858-7_4

Lupus brain fog: a biologic perspective on cognitive impairment, depression, and fatigue in systemic lupus erythematosus

This paper reviews potential biologic mechanisms for the cognitive impairment, depression and fatigue associated with systemic lupus erythematosus (SLE).

Summary
  • Patients with SLE frequently report cognitive impairment, fatigue and depression, which have a substantial impact on their quality of life.
  • The immune system and the brain are interlinked via several pathways: within the central nervous system (CNS) between neurons and between neurons and microglia, within the vasculature in various brain regions and within neuroendocrine pathways.
  • Data exists to support a role for adaptive immunity in normal brain function. The choroid plexus, a specialized interface between the brain and the peripheral circulation, acts as a mediator for neuroimmune interactions – an abundance of T cells in this area has been associated with worsening CNS and peripheral disease manifestations in mouse models.
  • Increased levels of peripheral circulating inflammatory cytokines are thought to mediate changes in central cytokine expression, leading to transient alterations in cognitive processes. This may occur in chronic inflammatory states such as in SLE, where organ damage related to immune dysregulation is mediated partly by peripheral circulating cytokines.
  • Idiopathic major depression has been associated with increased circulating levels of cytokines, and increased SLE activity has been linked to increased vulnerability to depression.
  • Central mechanisms that may play a role in the complex interplay between the immune system and cognition involve the cytokines, chemokines and neurotransmitters, with impaired adult neurogenesis also playing a possible role.
  • Autoantibodies present in SLE have also been implicated in cognitive disturbances and mood disorders. Cerebrospinal fluid autoantibody levels have been shown to correlate significantly with neuropsychiatric manifestations.
  • Evidence suggests that the chronic inflammation present in SLE, along with episodes of acute escalation, lead to altered CNS processing, with resultant effects on cognition and mood.

Mackay M. Immunol Res 2015;63:26–37. doi:10.1007/s12026-015-8716-3

Lung disease

The complex role of the lung in the pathogenesis and clinical outcomes of rheumatoid arthritis

This review highlights recent studies examining the relationship between antibodies to citrullinated protein/peptide antigens (ACPA) and other autoantibodies and lung disease in patients with rheumatoid arthritis.

Summary
  • Lung disease is a frequent manifestation of seropositive rheumatoid arthritis; some studies have suggested that up to 80% of rheumatoid arthritis patients have some form of lung disease.
  • Risk factors for lung disease in rheumatoid arthritis include smoking, environmental factors such as dust exposure, male gender, rheumatoid arthritis disease duration, disease activity, seropositivity for rheumatoid factor, infections and medication toxicity, and the presence of circulating ACPA.
  • ACPA may play a role in the development of lung disease, with one meta-analysis of 8 case-control studies showing a significant association between ACPA positivity and increased risk of rheumatoid arthritis lung disease (pooled odds ratio 2.62; P<0.01).
  • Development of rheumatoid arthritis-related lung disease is likely to involve gene-environment interactions, protein citrullination, impaired tolerance and the subsequent development of circulating autoantibodies, including ACPA.
  • There is some evidence to suggest that rheumatoid arthritis-related autoimmunity may be generated in the mucosa, with levels of rheumatoid arthritis-related autoantibodies shown to be elevated in the sputum of at-risk and early rheumatoid arthritis subjects, compared with healthy controls.
  • There are several mechanisms whereby autoimmunity that develops in the lung mucosa may reach the joints – including cells or autoantibodies targeting antigens that are shared between sites, development of new joint-specific autoimmune responses due to epitope spreading, and circulating immune complexes driving articular disease.
  • The existence of relationships between autoantibodies and lung diseases in other autoimmune diseases has been described, supporting the notion that the lung has a pathophysiologic relationship with autoimmunity.
  • An understanding of the very early processes that lead to the development of rheumatoid arthritis could lead to novel treatment approaches to lung disease and potentially even to the prevention of articular disease.

Kelmenson LB, Demoruelle MK, Deane KD. Curr Rheumatol Rep 2016;18:69. doi:10.1007/s11926-016-0618-4

Fatigue

Fatigue in rheumatoid arthritis

The paper reviews fatigue in patients with rheumatoid arthritis.

Summary
  • The prevalence of fatigue among patients with rheumatoid arthritis has been estimated at between 40% and 70%.
  • Measurement of fatigue in rheumatoid arthritis is not standardized.
  • The cause of fatigue in rheumatoid arthritis remains to be fully elucidated but it is likely to be multifactorial. Disease-specific factors likely to be associated with fatigue include inflammation, pain, joint symptoms and functional limitations.
  • Non-rheumatoid arthritis-specific causes of fatigue can be grouped into four major categories, psychological (mood disturbances), behavioral (sleep disturbance, obesity, low physical activity and reduced functional capacity), cognitive and other physiological (muscle wasting and weakness, comorbid conditions).
  • Drugs used to treat rheumatoid arthritis do not appear to have much effect on fatigue levels, rather physical activity interventions are likely to be of significant benefit in treatment of fatigue in patients with rheumatoid arthritis.
  • Further research is needed to determine the most appropriate way to measure fatigue, to investigate sources of fatigue, integrate information from other autoimmune and rheumatic diseases, develop effective interventions that are feasible in clinical practice, and to improve communication between patients and healthcare providers regarding fatigue.

Katz P. Curr Rheumatol Rep 2017;19:25. doi:10.1007/s11926-017-0649-5

Malignancy

Malignancy incidence in patients with psoriatic arthritis: a comparison cohort-based incidence study

This retrospective population-based cohort study investigated the malignancy risk in patients with psoriatic arthritis.

Summary
  • It is known that patients with rheumatoid arthritis have an increased risk of lymphoma and lung cancer, but the risk of malignancy in psoriatic arthritis remains to be determined.
  • The aim of this study was to determine the malignancy risk in patients with psoriatic arthritis.
  • The study was a retrospective, population-based cohort study, which included 217 subjects with psoriatic arthritis and 434 age- and sex-matched controls.
  • During follow up, a total of 43 patients in the psoriatic arthritis cohort were diagnosed with at least one malignancy compared with 70 patients in the control cohort, with a cumulative incidence of malignancy at 10 years of 12.3% in the psoriasis cohort compared with 8.6% in the control cohort (hazard ratio 1.41; 95% confidence interval [CI] 0.96, 2.07).
  • When non-small cell lung cancers were excluded, the risk of malignancy was significantly increased for psoriasis, with a hazard ratio of 1.64 (95% CI 1.03, 2.61).
  • Breast cancer was the only cancer site statistically more frequent in the psoriasis cohort, with a hazard ratio of 3.59 (95% CI 1.22, 10.61).
  • The increased risk of malignancy in this cohort demonstrates that the malignancy risk profile is altered in psoriatic arthritis.

Wilton KM, Crowson CS, Matteson EL. Clin Rheumatol 2016;35:2603–2607. doi:10.1007/s10067-016-3396-5

Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis

This systematic literature review investigates the risk of malignancy in patients with rheumatoid arthritis and provides an update to results of a previous meta-analysis investigating this relationship.

Summary
  • A meta-analysis on malignancy using data published between 1990 and 2007 suggested an increase in risk of malignancy, specifically for lymphoma, Hodgkin disease, non-Hodgkin lymphoma and lung cancer, in patients with rheumatoid arthritis compared with the general population.
  • The current study, a systematic literature review, was conducted to provide updated information on the incidence of malignancies in patients with rheumatoid arthritis, with a further nine studies published between 2008 and 2014 that met all inclusion criteria identified and analysed.
  • Six of seven studies reported a significant increase in overall risk of malignancy, with a total pooled standardized incidence ratio (SIR) for studies included in the previous meta-analysis and the more recent studies of 1.09 (95% confidence interval [CI] 1.06, 1.13).
  • Eight of the nine studies reported a significant increase in the risk of lymphoma in patients with rheumatoid arthritis. Total pooled SIRs for studies included in the current study combined with those from the previous meta-analysis for malignant lymphoma, Hodgkin disease and non-Hodgkin disease were 2.46 (95% CI 2.05, 2.96), 3.21 (95% CI 2.42, 4.27) and 2.26 (95% CI 1.82, 2.81), respectively.
  • Eight studies reported that patients with rheumatoid arthritis have an increased risk of lung cancer. The total pooled SIR was 1.64 (95% CI 1.51, 1.79) for lung cancer.
  • In seven studies, patients with rheumatoid arthritis were reported to have a decreased risk of colon or colorectal cancer, although two studies reported SIRs >1, and there was no general increase in risk for breast cancer.
  • The current study also investigated cervical cancer, prostate cancer and melanoma, with no consistent trend found for these cancers in patients with rheumatoid arthritis compared with the general population.
  • The authors postulate that the autoimmune pathogenesis of rheumatoid arthritis and common etiology between rheumatoid arthritis and malignancy may go some way towards explaining the increased risk of malignancy among patients with rheumatoid arthritis.

Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Arthritis Res Ther 2015;17:212. doi:10.1186/s13075-015-0728-9

Infection

Uveitis in spondyloarthritis including psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease

This paper provides a brief review of uveitis in patients with ankylosing spondylitis, psoriatic arthritis and inflammatory bowel disease.

Summary
  • Uveitis is a common and important condition in spondyloarthritis, particularly ankylosing spondylitis in which it has a prevalence as high as 50%. It is also important in psoriatic arthritis, affecting approximately 7% of patients, and in inflammatory bowel disease with a prevalence of approximately 2% to 5% of patients.
  • Genetic loci that affect the likelihood of uveitis development in patients with ankylosing spondylitis, separate from those affecting predispositions to joint disease, have been identified; these loci have yet to be studied in uveitis associated with psoriatic arthritis or inflammatory bowel disease.
  • The treatment of uveitis is complicated, with recommendations differing by severity of disease and its impact on daily life; options include prednisone, systemic immunosuppression or, less frequently, a tumour necrosis factor (TNF) inhibitor.
  • It has been reported that TNF inhibitors cause uveitis, but it is difficult to determine the nature of a link between uveitis in a patient with ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease and any medication, given that uveitis is commonly associated with the disease.
  • Uveitis is clinically important in terms of both treatment and of the understanding of the etiology of spondyloarthritis.

Rosenbaum JT. Clin Rheumatol 2015;34:999–1002. doi:10.1007/s10067-015-2960-8

The risk of hospitalized infection following initiation of biologic agents versus methotrexate in the treatment of juvenile idiopathic arthritis

This study used claims data to compare rates of hospitalized infection among children with juvenile idiopathic arthritis initiating treatment with a biologic agent versus initiating methotrexate treatment.

Summary
  • Findings of studies investigating the role of biologic agents in infection risk in patients with juvenile idiopathic arthritis (JIA) are inconsistent.
  • This study investigated rates of hospitalized infection in children with JIA by treatment type using US Medicaid claims data from 2000 to 2010; 3075 new users of methotrexate (160 of whom were assumed to have systemic juvenile idiopathic arthritis [SJIA]), 2713 new tumor necrosis factor (TNF) inhibitor users and 247 new anakinra users were identified.
  • At baseline, there were significant differences between the cohorts: TNF inhibitor users were older, and anakinra users had higher baseline use of glucocorticoids and more frequent primary hospitalized infections during the baseline period.
  • The most frequent types of hospitalized infection were pneumonia (19%), bladder and kidney (13%) and cellulitis and abscess (10%).
  • Newly initiated therapy with a TNF inhibitor as monotherapy or with methotrexate was not associated with a significant risk of infection compared with newly initiated methotrexate (with or without concurrent or prior biologic) - adjusted hazard ratios of 1.19 (95% CI 0.72, 1.94) and 1.23 (0.69, 2.17), respectively.
  • Factors associated with increased infection risk were primary hospital discharge of infection during the baseline period and use of high-dose oral glucocorticoids during the baseline period.
  • There was a significant association between anakinra use and risk of infection, compared with methotrexate use, although this increased risk was attenuated when compared with methotrexate use in those assumed to have SJIA.

Beukelmam T, Xie F, Baddley JW, et al. Arthritis Res Ther 2016;18:210. doi:10.1186/s13075-016-1109-8

Infections with biologics in rheumatoid arthritis and related conditions: a scoping review of serious or hospitalized infections in observational studies

This review focuses on the risk of serious infections in patients with rheumatoid arthritis receiving treatment with a biologic, with an emphasis on helping clinicians and patients make treatment decisions.

Summary
  • Patients with rheumatoid arthritis have been shown to have a higher rate of infections than non-rheumatoid arthritis patients, and a higher risk of hospitalized infections.
  • More active rheumatoid arthritis has been shown to be associated with an increased rate of hospitalized infections.
  • Tumor necrosis factor (TNF) inhibitor treatment has been shown to be associated with an increased risk of serious infections during the first 6 months of therapy, with this risk higher than that for traditional DMARDs for up to 24 months.
  • Regarding hospitalized infection, compared with non-use, current biologic use was found to be associated with significantly higher risk (relative risk 1.21; 95% confidence interval 1.02, 1.43).
  • Most serious infections occur within the first 1–2 years of biologic therapy.
  • In most analyses, infliximab, and in some cases adalimumab, was associated with an increased risk of serious infection compared with etanercept or rituximab, with abatacept having lower risk than infliximab or adalimumab.
  • Non-treatment-associated factors that may confer increased infection risk in rheumatoid arthritis include older age, diabetes, smoking, glucocorticoid dose and previous infection history.
  • The risk of infection must be discussed with patients when starting therapy. More research is needed to improve understanding of the risk of serious infection with each individual biologic agent based on individual patient profiles.

Singh JA. Curr Rheumatol Rep 2016;18:61. doi:10.1007/s11926-016-0609-5

Infection and lupus: Which causes which?

This review outlines current understanding of the relationship between the pathophysiology and treatment of systemic lupus erythematosus and infection risk.

Summary
  • Both the innate and adaptive immune systems are involved in the pathogenesis of systemic lupus erythematosus (SLE). There is also evidence for a role of genetics.
  • The risk of infection due to the immune dysfunction associated with SLE is further increased by the immunosuppressive agents used to treat SLE, especially the glucocorticoids as well as cyclophosphamide and rituximab. In contrast, anti-malarials may confer a protective effect.
  • Infectious agents have been implicated in triggering disease flares in SLE, but there is now evidence to suggest that these agents may play a role in the development of autoimmunity. Potential causative factors include Epstein Barr virus, cytomegalovirus, human endogenous retroviruses, parvovirus B19, mycobacterial tuberculosis, and bacterial amyloids.
  • In contrast, some organisms may protect against the development of SLE, these include Helicobacter pylori and Toxoplasma gondii.
  • The microbiome may also play a role in the development of SLE, with an imbalance of certain bacteria in the gut of those with SLE shown.

Doaty S, Agrawal H, Bauer E, Furst DE. Curr Rheumatol Rep 2016;18:13. doi:10.1007/s11926-016-0561-4